The present invention is directed to novel 2-arylthiazole compounds which are modulators of KCNQ potassium channels and are useful in treating disorders responsive to the modulation of the potassium channels. The invention also provides pharmaceutical compositions and methods of treatment with the novel 2-arylthiazole compounds.
Potassium (K+) channels are a diverse class of ion channels and have several critical roles in cell function. One role is in neurons, where K+ channels are responsible, in part, for determining cell excitability by contributing to membrane repolarization following depolarization, resting membrane potential, and regulation of neurotransmitter release. The M-current, measured by electrophysiology recording methods and by pharmacology, has been described as a dominant conductance in controlling neuronal excitability. Pharmacological activation or suppression of M-currents by small molecules could have profound effects in controlling neuronal excitability. Recently, Wang reported that co-assembly of the KCNQ2 and KCNQ3 potassium channels underlies the native M-current in neurons (Wang et al., Science 1998, 282, 1890-1893).
Activation or opening of the KCNQ channels, particularly the KCNQ2 or KCNQ2/3 channels, mutated or wild type, may be beneficial for increasing hyperpolarization of neurons, thereby resulting in protection from abnormal synchronous firing during a migraine attack. This invention provides a solution to the problem of abnormal synchronous firing of neurons related to migraine headache by demonstrating that modulators, preferably openers, of KCNQ potassium channels increase hyperpolarization of neurons. This leads to protection against abnormal synchronous neuron firing involved in migraine attacks.
Although the symptom pattern varies among migraine sufferers, the severity of migraine pain justifies a need for vigorous, yet safe and effective, treatments and therapies for the great majority of cases. A need exists for agents that can be used to combat and relieve migraine (and diseases similar to and mechanistically related to migraine), as well as prevent the recurrence of migraine. Also needed are abortive anti-migraine agents, effective in the treatment of acute migraine, as well as in the prodrome phase of a migraine attack. Thus, a clear goal in the art is to discover new, safe, nontoxic and effective anti-migraine compounds and their pharmaceutical compositions for use in anti-migraine treatments.
Because migraine afflicts a large percentage of the population, there is a need to discover compounds and agents that are useful in therapeutics and treatments, and as components of pharmaceutical compositions, for treating the pain and discomfort of migraine headache and other symptoms of migraine. This invention satisfies this need by providing compounds that function as openers of the KCNQ family of potassium ion channels and act as anti-migraine agents.
A number of thiazole derivatives have been disclosed. These references do not teach or suggest the compounds of this invention. See the following: WO 01/40207 A1, JP 04128275 A2, U.S. Pat. No. 5,244,867, U.S. Pat. No. 4,980,363, U.S. Pat. No. 5,846,990, JP 04049290 A2, WO 99/66925 A1, U.S. Pat. No. 5,888,941, U.S. Pat. No. 3,794,636, JP 57183768 A2, U.S. Pat. No. 5,057,142, U.S. Pat. No. 5,859,035, JP 02229190 A2, WO 98/28282 A2, WO 00/06085 A2, U.S. Pat. No. 5,614,520, U.S. Pat. No. 3,689,481, JP 01250379 A2, U.S. Pat. No. 3,872,124, U.S. Pat. No. 4,923,886, WO 99/59570 A1, WO 01/10798 A1, and WO 95/19972 A1.